|Trade names||Serzone, Dutonin, Nefadar, others|
|Other names||BMY-13754-1; MJ-13754-1|
|Main uses||Major depressive disorder|
|Side effects||Sleepiness, dry mouth, nausea, constipation, blurry vision, confusion|
|Typical dose||300 to 600 mg/day|
|Protein binding||99% (loosely)|
|Metabolism||Liver (CYP3A4, CYP2D6)|
|Elimination half-life||• Nefazodone: 2–4 hours|
• Hydroxynefazodone: 1.5–4 hours
• Triazoledione: 18 hours
• mCPP: 4–8 hours
|Chemical and physical data|
|Molar mass||470.01 g·mol−1|
|3D model (JSmol)|
Nefazodone, sold under various brand names, is a medication primarily used to treat major depressive disorder. Other uses include aggressive behavior and panic disorder. It is taken by mouth.
Common side effects include sleepiness, dry mouth, nausea, constipation, blurry vision, and confusion. Other side effects may include liver problems, suicide, bipolar disorder, seizures, and priapism. Safety in pregnancy is unclear. How it works in not entirely clear but may involved effects on 5-HT and norepinephrine within the brain.
Nefazodone was patented in 1982 and approved for medical use in the United States in 1988. It is available as a generic medication. In the United States it costs about 260 USD per month as of 2021. It is no longer commonly used.
It is started at a dose of 100 mg twice per day with the typical dose being 300 to 600 mg total per day.
Common and mild side effects include dry mouth (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and jaundice.
Nefazodone can cause severe liver damage, leading to a need for liver transplant, and death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years.By the time that it started to be withdrawn in 2003, nefazodone had been associated with at least 53 cases of liver injury, with 11 deaths, in the United States, and 51 cases of liver toxicity, with 2 cases of liver transplantation, in Canada. In a Canadian study which found 32 cases in 2002, it was noted that databases like that used in the study tended to include only a small proportion of suspected drug reactions.
Nefazodone is not especially associated with increased appetite and weight gain.
Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5-HT2A receptor and 5-HT2C receptor antagonist and weak serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).
|Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.|
Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor. It also has high affinity for the α1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the α2-adrenergic receptor and dopamine D2 receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the histamine H1 receptor, where it is an antagonist, and hence may have some antihistamine activity. Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anticholinergic effects.
Nefazodone is metabolized in the liver, with the main enzyme involved thought to be CYP3A4. The drug has at least four active metabolites, which include hydroxynefazodone, para-hydroxynefazodone, triazoledione, and meta-chlorophenylpiperazine. Nefazodone has a short elimination half-life of about 2 to 4 hours. Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively. Due to its long elimination half-life, triazole is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself. Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state. Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite. mCPP is thought to be formed from nefazodone specifically by CYP2D6.
The ratios of brain-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure. Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats. As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.
In 2003 Public Citizen filed a citizen petition asking the FDA to withdraw the marketing authorization in the US, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug. The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.
In April 2004, BMS announced that it was going discontinue the sale of Serzone in the US in June 2004 and said that this was due to declining sales. By that time BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand and Canada.
As of 2012 generic nefazodone was available in the US.
Society and culture
Nefazodone has been marketed under a number of brand names including Dutonin (AT, ES, IE, UK), Menfazona (ES), Nefadar (CH, DE, NO, SE), Nefazodone BMS (AT), Nefazodone Hydrochloride Teva (US), Reseril (IT), Rulivan (ES), and Serzone (AU, CA, US). As of 2017, it remains available only on a limited basis as Nefazodone Hydrochloride Teva in the United States.
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